Doxorubicin is a known anthracycline antibiotic described in U.S. Pat. No. 3,590,028. Doxorubicin is an antineoplastic agent of established clinical utility. Doxorubicin hydrochloride, available from Adria Laboratories, Inc., under the trademark Adriamycin.RTM., has been approved by the Food and Drug Administration for use in clinical research, and is one of the most powerful anticancer drugs available against numerous forms of cancer. The analogue, 4-demethoxydaunomycin is a known anthracycline antiobiotic which has been demonstrated to have antitumor activity, as reported in the article by Arcamone et al., Cancer Treatment Reports, Vol. 60, (7) pp. 829-834 (1976).
At present, doxorubicin is produced commercially from a soil fungus by a fermentation process. A suitable fermentation technique for preparing doxorubicin is described in U.S. Pat. No. 3,590,028. Such techniques are inherently expensive and limit the types of molecules that can be produced. Because of the inherent disadvantages of presently available commercial techniques for producing doxorubicin and related compounds, substantial effort has been devoted to developing processes for producing such compounds by chemical synthesis.
Techniques for the synthesis of anthracycline antibiotics such as doxorubicin are known. See, e.g., U.S. Pat. No. 4,244,880 to Alexander et al.; Krohn et al., Chem. Ber. 111, pp. 3823-3837 (1978); Krohn et al., Liebigs Ann. Chem., pp. 2011-2017, (1979); U.S. Pat. No. 4,021,457 to Kende et al.; and Kende et al., Journal of the Americal Chemical Society, Vol. 98, No. 7, pp. 1967-1969 (1976). None of the known techniques for the total synthesis of anthracycline antibiotics such as doxorubicin have yet been proven to be commercially successful. Because of the demand for, and scarcity of these compounds, a suitable synthesis technique is highly desired.
The present invention provides a practical technique for synthesizing compounds related to doxorubicin from readily available and inexpensive starting materials. Specifically, and in accordance with the present invention, doxorubicin related compounds may be synthesized from leucoquinizarin. In addition, the present invention provides valuable intermediate compounds that are useful in synthesizing compounds related to doxorubicin.